Time Stamps

  • 04:30 What is the daily risk of thrombosis if HIT Is left untreated?
  • 05:40 What happens during platelet activation?
  • 07:11 How long does it take for patients to develop for IgG antibodies to Heparin to form?
  • 10:00 Is HIT common?
  • 10:28  Who is at higher risk for HIT?
  • 11:48 Why does low molecular weight heparin have a lower risk for HIT than unfractionated heparin?
  • 15:30 Approach to thrombocytopenia
  • 17:44 How do medications cause thrombocytopenia?
  • 18:38 With medications, what is the time course between medication initiation and thrombocytopenia?
  • 22:20 What is the sensitivity and specificity of anti-PF4 antibody?
  • 23:58 How does the serotonin-release assay (SRA) work?
  • 29:10 What type of anticoagulant do you choose for treating HIT?
  • 31:58 Why is it important to not use warfarin in patients with platelet counts <150,000?
  • 33:32 What is the treatment duration for a patient has confirmed HIT?
  • 36:29 Dr. Cuker’s story and the Scarlet H
  • 39:07 Dr. Linkin’s Recap
  • 42:25 Dr. Linkin’s story
  • 44:37 Pearl 5: Throwback to coronary calcium scores

Show Notes

Pearl 1: Pathophys and Epidemiology 

  • HIT is as an antibody-mediated activation of platelets with heparin exposure that results in thrombocytopenia, and in some cases, venous or arterial thrombosis.
  • We care about HIT because it is associated with a 6% daily risk of thrombosis, amputation and death if left untreated. 
  • HIT causes thrombosis by activating platelets to release pro-thrombotic substances via a complex of heparin, platelet factor 4 (PF4), and antibody (usually IgG). 
  • It generally takes 5-10 days for people to develop antibodies against heparin to cause HIT. However, if people have been exposed to heparin in recent past, they may already have antibodies against PF4 and can have rapid-onset HIT after heparin exposure. 
  • The overall incidence of HIT ranges from anywhere between 0.1% to 5%, depending on the patient population and the type of heparin used. 
    • Surgical patients are at a higher risk than medical patients
    • Low-molecular weight heparin (e.g. enoxaparin) is less likely to cause HIT than unfractionated heparin 

Pearl 2: The 4T score

  • The 4T score includes the degree of thrombocytopenia, the timing of platelet decrease, the presence of thrombosis, and considering the likelihood of other etiologies of thrombocytopenia
  • Consider using a systematic approach to thinking about thrombocytopenia. 
    • 1st rule out pseudothrombocytopenia
    • Decreased production: liver disease (decreased thrombopoietin), bone marrow hypoplasia (from meds, toxins, infections, pregnancy), ineffective erythropoiesis (megaloblastic anemia, MDS), and bone marrow infiltration (cancer, infection, myelofibrosis)
    • Increased destruction: hypersplenism, ITP, the thrombotic microangiopathies (TMAs), and HIT
  • Many medications can cause thrombocytopenia without causing thrombosis. Be sure to review medications 1-2 weeks prior to thrombocytopenia, not 1-2 days prior. A database of drugs that have been reported to do this can be found here

Pearl 3:  Testing for HIT

  • The anti-PF4 antibody test is an ELISA-based assay that detects circulating antibody that binds to PF4
    • The sensitivity for a diagnosis of HIT is cited as 98-100%, while the specificity is in the 30-40% range.
    • The test’s poor specificity comes from people who form antibodies against PF4 that don’t activate platelets and therefore don’t cause thrombocytopenia or thrombosis. 
  • The serotonin release assay (SRA) is a much more specific test for HIT and is the gold standard for diagnosis currently.
    • The SRA measures serotonin release from platelets in a heparin-dependent manner 
    • The main limitation is that it usually takes several days or up to 1 week to result 
  • A Bayesian approach to the diagnosis of HIT can be found here 

Pearl 4: Treatment of HIT 

  • Stopping heparin is not enough. If you’re testing for HIT, generally you should be treating HIT with anticoagulation 
  • The type of anticoagulant is going to depend on a few different factors: how quickly you need to be able to reverse or turn off the anticoagulant (high bleeding risk, upcoming procedures, critical illness), and their liver and kidney function
    • Quick on/off, reversible: argatroban, bivalirudin
    • Slow on/off: DOACs (rivaroxaban, apixaban), fondaparinux 
    • Liver dysfunction: avoid argatroban 
  • Starting warfarin is contraindicated until platelet count has recovered to ~ 150k as it can increase the risk of thrombosis (HIT patients are very dependent on protein C to prevent thrombosis) 
  • Treatment duration depends on if the patient has HIT complicated by thrombosis, or isolated HIT. 
    • With HIT with thrombosis, treating as if they have a “provoked” clot for 3 months is appropriate. 
    • For HIT without thrombosis, there isn’t a real consensus, but treating at least until their platelet count recovers is what most hematologists recommend, and sometimes up to 4-6 weeks.  

Pearl 5: Throwback to Coronary Calcium Score 

  • Coronary calcium scoring should only be used to risk-stratify asymptomatic patients if the results may influence the initiation of primary prevention medications. 
  • Power of a calcium score of ZERO: statins are not associated with a reduction in major adverse events in this group and can consider discontinuing a statin.


M: This is Dr. Marty Fried, Dr. Shreya Trivedi, and Dr. Joel Money.  This is the CORE IM 5 pearls podcast bringing you high-yield evidence-based pearls. Today we’re discussing heparin-induced thrombocytopenia, which we’ll affectionately refer to as “HIT” for the remainder of the episode.

S: Basically everything an internists ever needs to know about HIT with a little extra sprinkles of heparin ah-has! and thrombocytopenia goodness

Dr. Cuker: If you look back in the literature a couple decades ago, so before you and I were in practice, the concern was raising awareness about HIT, the concern was missing cases of HIT. And while that still happens occasionally, I think that, um, we were so zealous with our educational campaign that we sort of pushed the pendulum may be a little bit too far. And so now I think a much more common problem than missing HIT is over suspecting, over diagnosing, and overtreating, which can lead to harm in and of itself. 

S: That’s  Dr. Adam Cuker, a hematologist and Director of the Penn Comprehensive Hemophilia and Thrombosis Program. You’ll also hear from Dr. Lori Linkins, a thrombosis consultant at McMaster University do the recap. Both were authors of the 2018 American Society of Hematology guideline on the diagnosis and management of HIT

M: To help us with this we have another new CORE IM friend joining us, Dr. Joel Money, an internal medicine resident from the University of Utah.  Go Utes! 

J: SO glad to be here with you guys. To get in the mood for this recording, I may have had “HIT Me Baby One More Time”, and “HIT Me With Your Best Shot” on repeat. No judgements. 

M: Or maybe the lesser known classic “I want HIT that way”

J: Just a classic 

S: Okay guys, let’s not break the microphones during this recording (lets rein HIT in). Let’s get started on the questions we’ll be covering, remember to test yourself after each of the 5 pearls. 

M: Remember, the more you test yourself, the deeper your learning gains.

Pearl 1: pathophys and incidence of HIT

S: Why should we care about HIT?  And which patients are at risk for developing it? 

Pearl 2: The 4T score

S: When should we suspect HIT? And what is your framework for working up thrombocytopenia?

Pearl 3: Testing for HIT

S: What are the different laboratory tests used to diagnose HIT, and how good are they? 

Pearl 4: Treating HIT 

S: What are the treatment options once a diagnosis of HIT is suspected? How long do we need to treat patients for? 

Pearl 5: Throwback pearl – Coronary Artery Calcium Score

S: When should we be using CACS? And what do we do with the results of the score?


J: So let’s get started with a case to set the stage. You’re taking care of a middle aged man with HIV and ESRD on dialysis who is in the hospital with sepsis from pneumonia. He is on multiple antibiotics and anti-retrovirals for the HIV, and on hospital day 7, his platelet count drops to 50,000 from his baseline of about 170,000 on admission. You bring this up on rounds and start talking about the differential diagnosis, and do everything you can to avoid saying “HIT” because you really don’t want to go down that rabbit hole…

M: Can’t we just say his thrombocytopenia is due to his sepsis or his multiple antibiotics and move on? I mean we have 19 other patients to round on before noon today and the med students haven’t even started their presentations yet… 

S: Oh I hear you! But here’s the sticky point…diagnosing HIT (or misdiagnosing HIT) can be devastating. 

Dr. Cuker: Left untreated, HIT is associated with about a 6% daily risk of thrombosis, amputation and death. And that is a really high risk when you think about it. I challenge you to come up with any other thrombophilic condition, inherited or acquired, that comes close to HIT in terms of how profoundly hypercoagulable it is.

M: Hey uhh Joel – what was that sound?!?

J: I think it was the sound of a mic being dropped somewhere… [M: Oh snap!] and to reiterate, that is a 6% DAILY risk! I had no idea that that was the case before going down this rabbit hole! 

S: Right so now that everyone’s ears are perked, we should back up a bit and explain what we actually mean when we say HIT

M: I feel a little pathophysiology nugget coming? 

J: You sure do! Generally put, HIT can be defined as an antibody-mediated activation of platelets with heparin exposure that leads to  thrombocytopenia, and in some cases, venous or arterial thrombosis

S: We’ll link to a diagram in the show notes and on social media. The essence of what is happening with HIT is the formation of a complex of 3 things:  first, you got heparin, a negatively-charged polysaccharide, which is attracted to platelet factor 4, which is a positively-charged protein stored in platelet granules and released during platelet activation, and last but not least, on top of that complex of heparin and platelet factor 4  is an antibody, usually IgG. We’ll call these “HIT antibodies”. 

M: So why is this complex important and what do they do? 

J: They do what we all learned about in medical school and promptly forgot after Step 1: activate platelets. 

Dr. Cuker: When a platelet becomes activated, it changes shape. It sort of goes from being kind of like a nice round shape to having almost like pseudopodia. And it releases the contents of certain granules into the circulation. And these granules contain a number of different molecules, but some of these molecules have the job of recruiting more platelets causing platelets to aggregate and again to become activated and secrete more of these molecules. And so you sort of have this positive feedback loop as more and more platelets can become activated and incorporated into potentially a thrombus.

J: So the thrombocytopenia is coming from both consumption of platelets at the site of thrombosis and from being activated, as well as being removed by our good ol’ friend the spleen after being coated with antibody. Pretty sure that’s the only thing a spleen is good for. 

S: Oh poor spleen! Ok it sounds like when heparin gets into someone’s blood in any way, it can bind to PF4. In some people, this can create an immune response in which antibodies are formed against this complex, causing platelets angry aka platelet activation. This generally takes about 5-10 days because it takes time for plasma cells to make antibodies and get them into circulation.

J: 5-10 days, unless, of course, they have rapid-onset HIT

M: whhaaaattttt…. I didn’t think this was supposed to get more complicated 

S: It turns out that is does. Rapid-onset HIT is when  platelet counts precipitously drops after exposure to heparin and this is in patients have had prior exposure to heparin, usually within the last 30-100 days. Here we’ll let Dr. Cuker explain: 

Dr. Cuker: so most cases of HIT occur in patients who do not have preexisting HIT antibodies. We put them on Heparin, and if they’re going to develop HIT, it takes some time for those IgG antibodies to form. And specifically that, that time is about 5 to 10 days. And so you see the platelet count begin to fall by 5 to 10 days after initiation of Heparin. So that’s what we call sort of typical onset HIT, but the exception is that now imagine a patient who had heparin within the very recent past, let’s say, um, hospitalization two weeks ago. And that Heparin caused the patient to form HIT antibodies. Um, but by the time those HIT antibodies formed, they were no longer on Heparin. And so the HIT antibodies didn’t cause any trouble because there were no platelet factor four Heparin complexes around for the antibodies to bind to, uh, leading that activation of platelets and thrombosis. And so the patient made antibodies, nobody knew about it. Now they get readmitted to the hospital and they are given heparin again, but now the antibodies are already in circulation. And so when they get Heparin, it forms these multi molecular complexes with platelet factor four. And the antibodies are there to bind to those complexes, uh, and leading to that plead with activation, uh, and, and the potential risk for thrombosis. 

M: And that rapid-onset HIT happens quickly, often within 24 hours! (median onset time 10.5 hours) 

J: Ok so whether it’s the rapid-onset HIT or the classic 5-10 day HIT – either one bring about 1 in 20 daily risk of thrombosis, amputation, or death… which is crazy, but remember, HIT is rare.

Dr. Cuker: HIT, is uncommon, but very commonly suspected. As a hematologist, I can tell you that the most common consult we get in the hospital is, um, for suspected HIT. Most of those cases turn out not to be true HIT, but people are certainly thinking about it, which is good.

S: I am sure thinking about it! But looks like overall incidence ranges from anywhere between less than 1 to 5%, so which patients are  higher end of the spectrum and at risk for HIT?

J: There seems to be a difference between medical and surgical patients, with surgical patients being at a higher risk for developing HIT. 

S: What about the type of heparin used? I still have to  chart review but i’m pretty sure our patient was on SQ heparin for DVT ppx

M:  And we often forget that people on dialysis are exposed heparin because it’s used to keep the juices going within the dialysis circuit

J: As you’re pointing out, the type of heparin definitely makes a difference. Unfractionated heparin gives a higher risk than low molecular weight heparin. There’s a nice Cochrane systematic review from 2017 that included 1400 post-op patients randomized to receive either unfractionated heparin or low molecular weight heparin and  found about an 80% lower risk of HIT with low molecular weight heparin compared to Unfractionated Heparin.

M: That difference is no joke! 

S: I love another reason to put patients on low molecular weight heparin! Its once a day injection vs. 2x and 3x a day heparin SQ and less costly 

M: Do we know why unfractionated heparin has such higher risk for HIT? 

Dr. Cuker: The pathogenic complexes, form most readily with larger strands of Heparin. As the pieces of Heparin get smaller, you’re less and less likely to form these large multi molecular pathogenic complexes. So we see it less frequently with, for example, low molecular weight Heparin, and then it’s vanishingly rare with fondaparinux, which is just the sort of the five sugars, the Pentasaccharide part of Heparin.

S: Fascinating now that i understand the pathophysiology – it kinda makes sense unfractionated heparin is a bigger strand has more room for the pathogenic complexes to form on but  low molecular weight heparin is smaller, less room for mischievousness complexes. OK thats the type of heparin, what about dose of heparin? Does it even matter if it’s therapeutic or prophylactic heparin? 

J: So there doesn’t seem to be a difference in the incidence of HIT between therapeutic and prophylactic dosing of heparin. Marty, to keep the ants on a log thing going, it doesn’t matter how many celery sticks are floating around, but it truly is how long the stick is that matters. 

M: Yes! I’m chalking this one up in the win column! OK let’s try to wrap up the first pearl.  HIT is an antibody-mediated activation of platelets – it begins with this formation of PF4-heparin-Ab complex that then triggers a platelet activation cascade and the formation of more complex.  It’s a relatively rare diagnosis has significant morbidity and mortality associated with it – remember we’re talking 6% risk of thrombosis, amputation OR death PER DAY! But that risk isn’t uniform across patients – medical patients getting low-molecular weight heparin are at the lowest risk, while surgical patients receiving UFH are at the highest risk, which tops out at about 5%. 


J: Back to our patient whose platelets are dropping. Remember we said he’s at about 50,000 right now and was at 170,000 about 1 week ago. He’s a nonsurgical patient on the medicine floors receiving UFH, which puts him in the middle of that 1-5% range based on what we just talked about. If only there were an objective way to measure his risk beyond basic gestalt… 

S: There’s that validated scoring system , the 4 T score that everyone learns about the at some point in med school- its  four components that (mostly) start with “T” to help consider the probability of HIT in patients with thrombocytopenia in the hospital. 

M: No need to memorize the scoring system, but you should know the four T’s refer to 1. degree of thrombocytopenia, 2. timing of platelet count fall, 3. presence of thrombosis, 4. and other possible causes for the thrombocytopenia. 

J: The trickiest part of the scoring system for me is the final part which tries to quantify how likely other diagnoses in our differential are. A lot of our patients have a bunch reasons why their platelets may be dropping like our patient. And the reason why it’s important to tease this out, remember, is that HIT has one key clinical difference that separates it from other causes of thrombocytopenia – that’s the risk of thrombosis.

Dr. Cuker: Most of those other thrombocytopenic disorders, they’re actually associated not with an increased risk of thrombosis, but primarily with increased bleeding risk. And if you were to treat those as though they had HIT, you would be subjecting them to the potential bleeding risks of the, the anticoagulants that we use to treat HIT without any benefit.

S: So if thrombocytopenia and clotting, it’s more likely to be HIT but if its thrombocytopenia and not clotting its open season? Is it the Vanc he is on? Is it sepsis induced thrombocytopenia? Is it post-viral thrombocytopenia? So many questions!

M: So many questions! First you gotta look at the smear and rule out platelet clumping r but then after, its good to have a systematic way to think about thrombocytopenia in hospitalized patients.  We’re going to give a huge shoutout to the great Dr. Andre Mansoor’s recent book “Frameworks for Internal Medicine”. He proposes 2 big buckets of thrombocytopenia include decreased production of platelets and increased destruction of platelets. 

J: Listeners take a pause and think about what causes decreased production of platelets……… Shreya, can you be my guinea pig  with the decreased production

S: Production of platelets is dependent on the liver and bone marrow so the first is there liver disease? (liver makes thrombopoietin aka TPO, and so in liver disease theres less TPO to help make platelets, similar to EPO that makes RBC), the second would be bone marrow hypoplasia (from meds, toxins, infections, pregnancy), third would be ineffective erythropoiesis (megaloblastic anemia, MDS), and lastly bone marrow infiltration (cancer, infection, myelofibrosis). 

J: 5 stars! What about increased destruction of platelets?

S: We are mostly thinking about hypersplenism, ITP – another immune mediated process from drugs, and less common things like, DIC, the thrombotic microangiopathies (things like TTP, HUS, atypical HUS), and last but not least, HIT falls under the destruction of platelets bucket!

M: probably the most helpful thing to start with is thinking about what drugs we are giving this person to make their platelet count drop. Mechanistically, this happens in a couple of different ways: 

Dr. Cuker: Some drugs cause thrombocytopenia through bone marrow suppression. And here the classic example would be like chemotherapy. Um, and most of those drugs do not cause isolated thrombocytopenia. They cause a reduction in all blood cell counts. The kind of drug induced thrombocytopenia that I think is most often mistaken for HIT is drug induced immune thrombocytopenia where the patient makes antibodies that attack and clear their platelets in the presence of a particular drug. And there are so many drugs that have, uh, been accused of causing this particular condition. 

M: There happens to be a great database of drugs that commonly cause drug-induced thrombocytopenia which we will link to in the show notes.

S: Here the most important piece of the puzzle is the time course for the drop in platelets. Dr. Cuker describes one of the most common mistakes internists make when reviewing the time course of the platelet drop: 

Dr. Cuker: One of the common mistakes that I see is that when somebody thinks that a drug might be to blame for a fall in platelet count, they say, okay, well the patient’s platelet count started to fall on Tuesday. So what drugs were started on Monday, but that’s actually not the time to be looking. It was a week ago, Monday or two weeks ago, Monday. Those drugs that were started a week to two weeks before the platelet began to fall, those are the ones that should be suspected. 

J: Bummer, it’s so much easier to just scroll through the administered meds for 1-2 days! But really, we need to scroll back 1-2 weeks for drug-induced thrombocytopenia. 

S: Right there other things the patient has been exposed to than heparin! While its really great to go through this framework and think about the different causes, one of the things i was really hoping in producing this episode was having more clinical pivot points that can help push us towards one cause of thrombocytopenia vs. the other but both the hematologists we talked to said:

M: Oh my gosh there’s so much to consider, but this is fantastic to talk through. Let’s review this pearl.  When considering the diagnosis of HIT use the 4T score – degree of thrombocytopenia, timing of thrombocytopenia, presence of thrombosis, and – similar to the Well’s criteria – the last question asks about alternative explanations to thrombocytopenia.  For that we gave a shoutout to Dr. Mansoor’s framework – decreased production bucket and increased destruction bucket. And review medications that were started 1-2 weeks before development of thrombocytopenia, NOT just 1-2 days.  

J: Nice recap Fried.  Alright let’s calculate a 4T score for our patient: 2 points for the degree of thrombocytopenia, 2 points for timing, 0 points for thrombosis, and let’s say 1 point for other causes of thrombocytopenia. That gives us a score of 5, or intermediate risk. What do we do now? 

S: Sounds like a great time to move on to Pearl #3.


J: So we’ve been talking about our patient’s thrombocytopenia for 10 minutes on rounds already, med students still have not presented yet and I’m ready to move on. Intermediate risk 4T score. Consult heme. Done. Right? 

S: Now now, we can figure this out. Let’s talk about what kind of testing we can use to figure out if our patient actually has HIT. 

M: There are 2 main kinds of laboratory tests for HIT: one test is used to detect the presence of antibodies, and another test used to see if the antibodies are functionally active or activating platelets.

J: Let’s start with the first test to detect antibodies. The anti-PF4 antibody test is an ELISA-based assay that detects circulating antibody that binds to PF4. 

S:  And if anyone needs clarification, just remember PF4 is a protein that is stored in platelets and is released during platelet activation.  

J: It turns out that Anti-PF4 test is extremely sensitive, but not super specific. The sensitivity if often cited as 98-100%, while the specificity is in the 30-40% range.

S: So a PF4 antibody is a great test to RULE OUT HIT, but if it’s positive, it doesn’t necessarily mean they have HIT. One study found that 8-17% of people who received some sort of heparin product for 7 days had positive HIT antibodies without actually having clinical HIT (i.e. they don’t become thrombocytopenic and they don’t form thrombosis) 

J: Would a good analogy be like a d-dimer? 

M: Exactly – the d-dimer being a very sensitive test to rule OUT VTE in patients that are low-moderate risk. Same thing with the anti-PF4 antibody. A negative test is reassuring that the patient doesn’t have HIT. 

S: There is one important caveat to anti-PF4 antibody’s specificity. There are essentially gradations of positivity, which you can think of like the titer of antibody. This is referred to as the optical density (OD). The standard cutoff for a “positive” OD is generally around 0.6. So less than 0.6 is negative, and greater than 0.6 would be positive in most laboratories. 

J: The reason why we even care about this in the first place is because, while there is a confirmatory test, if the OD is super high, like >2.0, the likelihood of HIT goes WAY UP which will make us much more compelled to treat as if it is actually HIT. 

S: Buuttt, like a d-dimer most are going to be frustratingly positive but low, and the main thing we’re really trying to figure out is if these antibodies that we just detected are actually causing platelet activation. That’s the job of the confirmatory serotonin-release assay. 

Dr. Cuker: So we, we collect platelets from donors and we radio label their platelets, uh, with, with C14, and this C14 gets incorporated into serotonin, which is stored in the dense granules of platelets. And it turns out that when platelets become activated, they release the contents of their dense granules into the circulation and we can, um, measure the release of this radioactive serotonin. 

S: Makes so much sense now why they call it serotonin release assay  – more like “platelets are being activated and something is making them angry” assay

J: So angry!! But why do we even need to send the screening PF4 antibody if there is a confirmatory test? The SRA sounds like a nice easy straightforward test to perform.

Dr. Cuker: it requires fresh donor platelets and radioactivity every time you do the test. And for most clinical laboratories, those are not feasible reagents. And so therefore tests like the serotonin release assay is really only offered at select reference laboratories around the world. And most of us, when we want to order an SRA, we have to send it out to a reference lab and we get the results back, you know, in a week.

J: Ok, nevermind. Guess we’re stuck waiting for a week for the SRA result to come back…

M: The SRA is much more specific test and for our purposes a positive result confirms the diagnosis of HIT. 

S: So let’s put this all together. We have a 4T score, an anti-PF4 antibody test, and a serotonin-release assay. In what order should we be doing these tests, and how should we be interpreting the results? 

M: There’s a great chart from Dr. Cukers article that we put in the show notes to follow along. First, calculate a 4T score. If it’s low risk (i.e. score of 0-3), stop. It isn’t HIT, pick up a copy of Mansoor’s book and start considering other diagnoses… 

J: If it’s intermediate risk (i.e. score 4-5), then we need to at least consider HIT. One study found the incidence of HIT with an intermediate score to be around 14%. At this point, send an anti-PF4 antibody test. If the OD is <0.6, stop. It’s not HIT. Consider other diagnoses. If OD is between 0.6 and 2.0, send the SRA and stop heparin. We’ll get into the treatment options in just a bit. 

S: If it’s high risk (i.e. score 6-8), then the incidence of HIT is much higher, around 65%. Here we will still send the anti-PF4 antibody and the Serotonin Release Assay. And if the Ab is negative, you are not dealing with hit and you can stop the alternative AC which we will get to in a minute.

M: Love it – OK, quick summary of Pearl 3: Two tests for HIT.  First is the highly sensitive anti-PF4 Ab. Second is the highly specific “platelets are being activated and something is making them angry assay” – also known as the serotonin release assay.  In general the algorithm should go 4T followed by anti-PF4 Ab test to serotonin release assay… but in reality we acknowledge that we often send both tests are at the same since you’re going to get the anti-PF4 Ab first and then the serotonin release assay a few days later..  

S: So back to our intermediate-risk patient: we send an anti-PF4 antibody and it comes back positive with an OD of 1.0. Since is less than 2.0 we’re waiting for the SRA to result. WHile we are waiting on that confirmatory test, what do we do in the meantime? 


J: So we think our patient might have HIT. And now we’ve officially gone down the rabbit hole and can’t come back out until the SRA comes back. 

S: Right, the obvious first step is to stop heparin, but do we really need to start him on different anticoagulation? Can’t we just get away with stopping the subq heparin our patient is on?

M: So part of me wants to say yes, but I have Dr. Cuker’s stat rattling around that every day that you delay initiation of therapy, which means stopping heparin and starting an alternative anticoagulant you expose the patient to about a 6% daily risk of thrombosis, amputation, and death.

S: Right. Gah – 6% daily risk of thrombosis! So… if you’re going to send diagnostic testing for HIT, we really need to be treating this as if our patients do have HIT. 

J: So in thinking about which actual alternative anticoagulant to choose, it turns out that there’s a lot more than just argatroban. 

S: Really? Okay, so I don’t have to feel guilty about putting my patients through  q 6 hours PTTs for argatraban?! 

M: Best. News. Ever. 

M: In terms of alternative anticoagulants, there are four main options: argatroban, fondaparinux, bivalirudin and direct oral anticoagulants aka the DOACs. Argatroban and bivalirudin are infusions. Fondoxaparinx is a once a day subcutaneous injection and when we talk about DOACs we’re really talking about rivaroxaban for really no other reason than it’s the best studied… 

J: There are some nuances to dosing intensity if your patient is at a particularly high bleeding risk – check out Dr. Cuker’s HIT guidelines that we’ll link to in the show notes. But in terms of the type of anticoagulant  you choose is going to depend on a couple different factors, and here we’ll let Dr. Cuker explain: 

Dr. Cuker: For example, if I had a patient who, um, that was I judged to be at greatly increased bleeding risk or, um, was at high risk of needing sort of urgent, unplanned procedures that would require stopping anticoagulation. Um, if I had a patient with multiorgan dysfunction and critical illness, those are the sorts of patients where I want to use a short acting drug like argatroban or Bivalirudin that can be quickly turned off. If specifically among those group of patients, if the patient has liver dysfunction, I might prefer bivalirudin because argatroban is metabolized in the liver. On the other hand, if I have patients who have good organ function, they’re clinically stable, maybe they’re even looking like they’re ready or getting close to being ready for discharge. Those are patients that I would preferentially treat with, either fondaparinux or a DOAC. Um, and they can even just go home on the drug. So really facilitate a transition to the outpatient setting.

S: Nice so for the acute treatment of HIT, we’re gonna go with argatroban or bivalirudin especially for high risk and/or upcoming procedure patients, and for stable patients, it’s gonna be fondaparinux or direct oral anticoagulants (DOACs) for stable patients, particularly rivaroxaban unless your local pharmacist tells you new studies have come.

J: Yeah by the time this airs, there will be a new RCT or something.

M: Well, what about warfarin? As much as I love getting people off the coum many of our patients can’t afford DOACs and are stuck with INR chasing.

J: With warfarin, you need to be VERY careful with initiation. The 2018 ASH guidelines strongly recommends AGAINST starting warfarin until the platelet count recovers to >150,000. 

Dr. Cuker: It is really important not to use warfarin in these patients and that is because patients with HIT, really need their protein C, uh, to prevent thrombosis. And, um, there have been terrible cases of patients with HIT, um, being treated with warfarin and developing absolutely devastating, uh, thrombosis. It’s, it’s uh, something called, uh, uh, limb gangrene. Um, and it’s very similar to, um, the warfarin induced skin necrosis that you, you may have learned about. So, um, who is an absolute contraindication to use warfarin in somebody with acute HIT. And in fact, if you, um, should ever be taken care of a patient with acute hit who, who may be who already was started on warfarin before the hit was diagnosed, you stopped the Warfarin and you give the patient vitaminK so that they can get their, their protein C back as fast as possible.

S: Heard that loud and clear. No warfarin if suspicious for HIT and if warfarin happened to be given, pump em with vitamin K.

M: Back to our patient: his sepsis has been pretty mild, his pneumonia has been improving and he is not planning on having any major procedures coming up. I suppose that qualifies him for either a DOAC or fondaparinux kinda guy? 

S: Let’s say we go with rivaroxaban for our patient then and the SRA also comes positive. How long do we need to treat him for?

J: This will depend on if the patient has HIT complicated by thrombosis, or isolated HIT. If they have HIT and a clot in an artery OR a vein, you can think about it kind of like a  “provoked clot”, similar to a provoked DVT, and treat for 3 months. 

S: And if the doppers are negative and there are no clots?  

J: For HIT without thrombosis, there isn’t a real consensus, but treating at least until their platelet count recovers is what most hematologists recommend. Sometimes this is up to 4-6 weeks, but there isn’t a solid recommendation about this.

S: Great so we discharge him on rivaroxaban with close hematology follow up to recheck the platelets. But what should we be educating our patients on discharge?  Should we tell him he should NEVER get heparin ever again?!

M: For the most part, heparin should be avoided, but it isn’t absolutely contraindicated. These are situations where you will want to involve your friendly neighborhood hematologists to help you out if you’re in a bind.

J: This was surprising to me.  For example, some patients undergoing cardiac or vascular surgery have little choice other than heparin for intraoperative anticoagulation.  A small study from 2014 looked at 20 patients with a remote history of confirmed HIT (mean 4.4 years after diagnosis) who were given heparin as part of cardiac or vascular surgery intraoperatively. Only 1 of the 20 developed clinical HIT after exposure, while 19 did not.  

M: I might take those odds… I hope I don’t have to take those odds, but I suppose I’d take them if I had to…

S: Either way, this  prolly getting out the generalist internists wheelhouse and would involve a hematologist peri-surgery.

M: Alright, lets recap Pearl 4, treatment of HIT.  In general, if you are concerned enough to be sending the PF4 antibody you should be considering treatment.  Treatment is at least discontinuing heparin but also starting a non-heparin anticoagulant. Choices here are argatroban and bivalirudin if you need something quick on quick off, or if the patient is stable and ready for discharge fondaparinux or rivaroxaban are your go-tos. Remember to avoid argatroban in liver dysfunction and avoid warfarin in pretty much all HIT patients until their platelets have recovered to 150,000. Remember that inhibition of protein C by warfarin can cause some badness in patients with HIT. 

S: Treatment duration should depend on if they have thrombosis or not – if so treat it like a provoked clot and if not at least until platelets recover.  Finally, those with a history of HIT should probably avoid heparin in the future…

Dr. Cuker: One of the things that I tried to impress upon my fellows is that every bit is important as being able to recognize HIT is being able to recognize not HIT.  And so this was a woman with Marfan Syndrome who had had, uh, a history of aortic valve replacement and she was on Warfarin and she was admitted to the hospital for a diarrhea, um, that had been going on for the last several weeks and she needed a colonoscopy. And so they admitted her to the hospital, um, for a workup. Her warfarin was stopped as she was bridged with unfractionated Heparin for the procedure. And it turns out that this woman had fluctuating low platelet counts due to something called pseudo thrombocytopenia, which is platelet clumping in, in lavender top tubes, um, a totally non pathologic condition. But, um, it was mistaken for true thrombocytopenia by the team. Um, and so they were concerned about the possibility of hit and so they stopped Heparin. They put her on argatroban. They ordered HIT laboratory testing and low and behold her HIT the Eliza came back weakly positive and the team interpreted that as definitive evidence that she had HIT. And so she ended up staying in the hospital, while she was being bridged back from argatroban to Warfarin. But as if sort of getting the diagnosis wrong wasn’t bad enough. Um, she had heparin added to her allergy list in the electronic record, and I call this the scarlet h. It’s like once you have that heparin allergy in the chart, you’re being branded with a scarlet h and it’s very hard for it to ever go away. And so what I discovered in the course of my research is that this woman had eight subsequent admissions to our health system. Each time she was denied Heparin because of this erroneous HIT or Heparin allergy that was listed in her chart a number of these times, she was treated with argatroban. She had two episodes of major bleeding on argatroban. And spent, you know, collectively numerous extra days and weeks in the hospital because of this mistake. And, and so what I would just urge listeners to consider is that while, diagnosing HIT promptly, instituting appropriate therapy is really important. It’s just as important to get the diagnosis right when the patient doesn’t have it to avoid misdiagnosis, inappropriate therapy and all that adverse downstream consequences that can arise as a result of that.

And before we get to the throwback pearl, we will go to Dr. Lori Linkin for the recap and her own story with a different twist.


J: So guys, I was thinking we could throw back to our 5 Pearls on coronary artery calcium scores and CT angiography

M: You talking stress bombs Joel?!?

J: You know it! such great episodes on cardiac stress testing. If you haven’t already, give these 2 episodes a listen. 

M: So let’s organize our diagnostic testing schema by remembering the 2 big buckets of testing for CAD: Functional tests and anatomic tests.  I feel like Reza and Rabih will be so proud of us Shrey dropping some schemas! 

S: Haha I agree.  With functional tests, we’re thinking of stressing the heart with exercise or medications and seeing what happens on EKG, echocardiography, nuclear imaging, or MRI.

J: And with anatomic testing, we’re trying to get a sense of what the coronary arteries actually look like with either coronary artery calcium scoring or coronary CT angiography. 

M: Alright do you guys remember which patients scenarios coronary artery calcium scoring would be most appropriate? 

S: Coronary artery calcium testing should only be used to risk-stratify asymptomatic patients, especially if it can help with your decision to start or not start statins. 

M: Can we get that classic clip of Greg’s warning… Greg saying his classic “i repeat don’t get this test if the patient has chest pain, i repeat…”

Greg: clip from CAC testing

M: Keep in mind there are a few classic situations where CAC scoring is super useful: The patient who is skeptical about starting a statin despite a ASCVD risk score in the teens, or maybe that a middle-aged patient with a risk score of 5.5% but with a family history of premature coronary disease.  

J: One of the biggest points I took away from that episode is the “power of zero” – that when the CAC score is 0, statins have not been shown to reduce major adverse cardiac events in that group. 

S: Yep! One of the few things in our arsenal to reclassify patients down to lower risk. 

M: Love when that happens. Its PCP gold right there. Alright folks that’s a wrap for us.  Hope you enjoyed the episode! 



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